Introduction to Retrosynthesis

At the beginning of each chapter, we'll explore how life-changing compounds, such as CRIXIVAN and Enalapril, are designed and developed. These and other important pharmaceuticals are typically synthesized through a strategic process called retrosynthetic analysis. Retrosynthesis is like reverse-engineering a layered cake: if you have a beautifully complex cake with multiple layers, you can think backward to identify the simpler ingredients needed to build the final cake.  The retrosynthetic arrow (typically depicted as a double-headed arrow pointing backward, like “⇒”) is a unique symbol in organic chemistry used to indicate retrosynthetic analysis. Unlike the regular reaction arrow (→), which represents the direction of a chemical transformation from reactants to products, the retrosynthetic arrow signifies the opposite: a conceptual backward-thinking process. It implies that we are breaking down a complex target molecule into simpler precursors rather than carrying out an actual reaction.  Here is our a three layer cake retrosynthetic analysis.

In retrosynthesis, chemists break down a complex molecule into simpler, more manageable starting materials, envisioning a synthetic path step by step. By deconstructing a molecule in this way, they can plan an efficient and practical route to construct the desired compound. To illustrate this, we’ll start with a simple example and then revisit how a key transformation—from Enalaprilat to Enalapril—was strategically developed to improve drug efficacy and bioavailability.

Aspirin Retrosynthesis

Now, let's put our retrosynthetic 'cake-baking' skills to the test with a familiar compound: aspirin. Imagine we want to 'bake' aspirin. Just like our layered cake, aspirin has distinct 'layers' or functional groups. We'll use our retrosynthetic arrow (⇒) to peel back these layers and identify the simpler 'ingredients' we need.

First, we see that aspirin (1) has an ester group. This 'layer' suggests that it was likely formed from a reaction between two simpler 'ingredients' or synthons: salicylate (2) and acetyl group (3).  Acetyl chloride (5) or acetic anhydride (6) are equivalents of an acetyl group. We can use our retrosynthetic arrow to represent this disconnection and a 'squiggly' arrow showing the bond we are disconnecting.  Do worry if you don't know the chemistry yet, you will learn them soon enough.

Then, we look at salicylic acid (4). While we could further break it down, for our simple 'cake' recipe, we'll recognize it as a readily available starting material. So, our retrosynthetic analysis reveals that to 'bake' aspirin, we need salicylic acid and acetyl chloride (or acetic anhydride). This backward thinking helps us plan the forward synthesis, where we combine these 'ingredients' to create our final product, aspirin.

Now that we've identified our 'ingredients,' let's see how we 'bake' aspirin in the lab.  The synthesis involves a simple reaction: we mix salicylic acid with acetic anhydride, often with a catalyst like sulfuric acid to speed up the reaction. This process, known as esterification, forms the ester linkage, resulting in aspirin. The resulting crystals are then purified, and we have our final product. Thus, our retrosynthetic plan has guided us to a straightforward and efficient synthesis of aspirin.